The estrogen receptor (“ER”) is a ligand-activated transcriptional regulatory protein that mediates induction of a variety of biological effects through its interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and estrones. ER has been found to have two isoforms, ER-α and ER-β.
Estrogens and estrogen receptors are implicated in a number of diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, as well as others diseases or conditions.
There is a need for new ER-α targeting agents that have activity in the setting of metastatic disease and acquired resistance (Jordan, V. (2003) J. Med. Chem. 46:883-908; Jordan, V. (2003) J. Med. Chem. 46:1081-1111; Riggs B. (2003) New Eng. J. Med. 348:618-629). Chromene-type selective estrogen receptor modulators have been described (Jain et al (2009) J. Med. Chem. 52:7544-7569; WO 2011/156518, U.S. Pat. No. 8,703,810; WO 2013/090829; WO 2013/090836; WO 2014/025138; WO 2014/205136; US 2006/0020018; U.S. Pat. No. 7,399,767; WO 2006/078834; WO 2006/042409; WO 2001/054699; WO 2001/026651; WO 2001/001969; WO 1999/063974; WO 1996/026201; U.S. Pat. No. 6,060,503).